Department of Biology, Faculty of Natural Sciences, Cell Death Research Laboratory, University of Haifa, Multi-Purpose Building, Mount Carmel, Haifa 31905, Israel.
Cell Death Differ. 2012 Feb;19(2):356-68. doi: 10.1038/cdd.2011.112. Epub 2011 Aug 26.
ARTS (Sept4_i2) is a pro-apoptotic tumor suppressor protein that functions as an antagonist of X-linked IAP (XIAP) to promote apoptosis. It is generally thought that mitochondrial outer membrane permeabilization (MOMP) occurs before activation of caspases and is required for it. Here, we show that ARTS initiates caspase activation upstream of MOMP. In living cells, ARTS is localized to the mitochondrial outer membrane. In response to apoptotic signals, ARTS translocates rapidly to the cytosol in a caspase-independent manner, where it binds XIAP and promotes caspase activation. This translocation precedes the release of cytochrome C and SMAC/Diablo, and ARTS function is required for the normal timing of MOMP. We also show that ARTS-induced caspase activation leads to cleavage of the pro-apoptotic Bcl-2 family protein Bid, known to promote MOMP. We propose that translocation of ARTS initiates a first wave of caspase activation that can promote MOMP. This leads to the subsequent release of additional mitochondrial factors, including cytochrome C and SMAC/Diablo, which then amplifies the caspase cascade and causes apoptosis.
ARTS（Sept4_i2）是一种促凋亡的肿瘤抑制蛋白，作为 X 连锁凋亡抑制蛋白（XIAP）的拮抗剂发挥作用，促进细胞凋亡。通常认为线粒体膜通透性改变（MOMP）发生在半胱天冬酶激活之前，是其必需条件。在这里，我们表明 ARTS 在 MOMP 之前起始半胱天冬酶激活。在活细胞中，ARTS 定位于线粒体的外膜。在凋亡信号的刺激下，ARTS 以半胱天冬酶非依赖性的方式迅速易位到细胞质中，在细胞质中它与 XIAP 结合并促进半胱天冬酶的激活。这种易位先于细胞色素 C 和 SMAC/DIABLO 的释放，并且 ARTS 的功能对于 MOMP 的正常时间至关重要。我们还表明，ARTS 诱导的半胱天冬酶激活导致已知促进 MOMP 的促凋亡 Bcl-2 家族蛋白 Bid 的裂解。我们提出，ARTS 的易位引发了第一波半胱天冬酶激活，从而可以促进 MOMP。这导致随后释放更多的线粒体因子，包括细胞色素 C 和 SMAC/DIABLO，然后放大半胱天冬酶级联反应并导致细胞凋亡。
